1. Field of the Invention
The present invention relates to a magnetic fluid detection method and magnetic fluid detection apparatus which are used to measure how a magnetic fluid possessing paramagnetism, that has been injected into an area adjacent to a malignant tumor, is distributed after a fixed period of time has elapsed, to obtain evidence for identifying sentinel lymph nodes, which are lymph nodes that are positioned on the downstream side of the malignant tumor site with respect to the direction of flow of the lymph, and that are located closest to the affected area along the lymphatic vessels that constitute the flow path of the lymph.
To describe this in more detail, the present invention relates to a magnetic fluid detection method and magnetic fluid detection apparatus which can measure the distortion of the local magnetic field distribution resulting from the fact that the specific magnetic permeability of a magnetic fluid possessing paramagnetism that has been injected into tissues is higher than that of the surrounding substance, and which can in non-invasive manner identify sites where large quantities of the magnetic fluid remain without being affected by external magnetic noise, by using a magnetic fluid possessing paramagnetism such as Feridex, which is a type of iron oxide colloid known as ultra-paramagnetic fine particles used as a magnetic marker, or using a paramagnetic fluid such as MnZn ferrite, Fe3O4 magnetite or the like, then injecting this magnetic fluid possessing paramagnetism from the outside into living-body tissues through which liquids can flow, then applying a direct-current or alternating-current magnetic field to the tissues constituting the object of measurement so that the magnetic fluid is excited, and finally measuring the local magnetic field gradient.
2. Description of the Related Art
Conventionally, in surgical operations performed on breast cancers, lung cancers, esophagal cancers and the like, not only has the malignant tumor area been excised, but all of the lymph nodes surrounding the site of the malignant tumor have been excised, i.e., purified, from the standpoint of preventing recurrence of the cancer due to metastasis. The reason for such purification of surrounding lymph nodes is that cancer cells exfoliated from the affected area are carried downstream with the flow of lymph flowing through the lymphatic vessels, leading to metastasis of the cancer.
However, in the case of excision of surrounding lymph nodes, there is a danger that this will cause immune suppression in the convalescent patient, so that it is desirable to forgo such excision if possible. Accordingly, procedure known as sentinel lymph node biopsy has been devised. Sentinel lymph nodes refer to the lymph nodes that are closest to the malignant tumor site along the lymph flow path among the lymph nodes positioned on the downstream side of the malignant tumor site with respect to the direction of flow of the lymph. The sentinel lymph node biopsy refers to a biopsy in which these sentinel lymph nodes are excised and examined in order to determine whether or not cancer cells are present in these lymph nodes. If cancer cells have not reached the sentinel lymph nodes, then the malignant tumor has not progressed to the stage where cancer metastasis occurs. Accordingly, cancer cells have naturally not migrated to any of the other lymph nodes located even further downstream in the direction of flow of the lymph, so that there is no need to purify the lymph nodes. Specifically, in this case, lymph nodes other than the sentinel lymph nodes are preserved.
However, it is not always the case that the lymph nodes that are closest to the malignant tumor site in terms of distance are said sentinel lymph nodes. The lymph nodes that are closest in terms of distance are lymph nodes that are positioned on the upstream side with respect to the direction of flow of the lymph and the lymph nodes are not necessarily said sentinel lymph nodes. This depends largely on how the lymphatic vessels, which form the flow passages of the lymph, are connected. Furthermore, the lymph is colorless and transparent, and the lymphatic vessels are also extremely fine, so that identification of the sentinel lymph nodes from the direction of flow of the lymph and positional relationship of the lymph nodes is virtually impossible by visual inspection during the limited time available in the surgical operation.
Recently, in the United States, methods using radioactive isotopes and dyes have been devised in order to identify the positions of sentinel lymph nodes, and such methods have already been practical use as biopsy methods in breast cancer. In such methods, a radioactive isotope or dye is used as a marker in the area proximal to the malignant tumor; a fluid containing this isotope or dye is injected, and sentinel lymph nodes are identified by investigating the position of the radioactive isotope or areas colored by the dye after a fixed period of time has elapsed. It is necessary that the particle size of the marker be approximately 10 nm or less, which is a size that can easily be pushed downstream by the flow of the lymph through the lymphatic vessels. The position of a radioactive isotope can easily be investigated using a miniature Geiger counter, and the amount of accumulation can also be roughly judged by the intensity of the radiation. Accordingly, such methods have made it possible to identify sentinel lymph nodes by means of a simple examination using the fact that said marker shows the greatest accumulation in sentinel lymph nodes as evidence.
In Japan, however, the handling of radioactive isotopes in hospitals is restricted by law, and the number of hospitals that have received permission to use such isotopes is extremely small. Accordingly, there are difficulties in the popularization of sentinel lymph node biopsy methods that use radioactive isotopes as markers. In the case of dyes, furthermore, there may be cases in which discrimination is difficult, depending on the condition of the living-body tissue. For example, since lymph nodes in the lungs are black due to the settling of carbon particles, visual discrimination is extremely difficult in the case of dyes.
Furthermore, a SQUID magnetic flux meter using a superconducting quantum interference device (hereafter abbreviated to “SQUID”) which can detect magnetic flux equal to approximately 1 in 1,000,000,000 parts of the earth's magnetism with high sensitivity has been applied in various fields, and in recent years, a high-temperature superconducting SQUID which can be utilized for cooling at the temperature of liquid nitrogen has been practical use. A method for identifying sentinel lymph nodes by using a magnetic fluid containing fine magnetic particles with residual magnetization characteristics as a magnetic marker, temporarily magnetizing this magnetic fluid by means of a strong magnetic field from the outside, and identifying sentinel lymph glands by utilizing the fact that the magnetic field arising from the residual magnetization is maintained for a short time, has been proposed by Mr. Saburo Tanaka et al. of Toyohashi Technical and Scientific University on Jan. 25, 2000. Details are reported in “Applications of High-Temperature Superconducting SQUID Microscopes in the Fields of Biotechnology and Medicine”, 66th Research Conference Materials of the 146th Committee for Superconducting Electronics of the Japanese Society for the Promotion of Technology. According to the home page of the Chubu Science and Technology Center (Ltd.), this is currently being studied (as of Oct. 8, 2001) as a part of subsidy work performed by the Japanese Society for the Promotion of Bicycles. However, this method involves many problems as described below.
As the particle diameter of the magnetic particles becomes smaller, the magnitude of the residual magnetization also decreases. In the case of a particle size (diameter) of 10 nm or less, which allows easy flow through the lymphatic vessels, the residual magnetization characteristics are almost completely lost in the case of almost all known magnetic materials, so that a magnetic sensor with ultra-high sensitivity must be used in order to measure the extremely weak residual magnetism. Since an extremely weak magnetic field is measured and the measurement is also susceptible to the effects of magnetic environmental noise, measurements must be performed in a high-performance magnetically shielded room. Not only are such magnetically shielded rooms expensive, but the magnetic noise radiated by other necessary medical equipment causes interference, so that such a method is inconvenient.
Furthermore, even if the ultra-high-sensitivity magnetic sensor that is used is a high-temperature superconducting SQUID, the cooling must be performed at the temperature of liquid nitrogen, so that the sensor unit is increased in size, and also has a considerable weight, whether the cooling system used is a liquid cooling system or a refrigerator using the heat cycle of a cooling medium. Accordingly, such a system cannot be carried and operated with one hand.
Furthermore, the magnetization of the magnetic fluid must be performed so that the direction of the residual magnetization is oriented along the direction of flow of the lymphatic vessels. If this is not done, the direction of the magnetic moment quickly becomes disordered as a result of the properties of the liquid and molecular motion, so that the magnetic moment as a whole drops, thus making measurement impossible. In order to maintain the direction of magnetization of the magnetic fluid for a long period of time, excitation must be performed with a solenoid coil wrapped around the lymphatic vessels. However, the actual lymphatic vessels themselves are difficult to distinguish by visual inspection, and even assuming that visual discrimination is possible, this method involves work such as the excision of tissue and attachment required in order to wrap the coil. Moreover, considering the difficulty of insulation measures that are required in order to prevent the exciting current, which is a large current, from flowing through the human body, this method is not suitable for practical use.
Meanwhile, an ultra-paramagnetic fluid possessing the paramagnetism of an iron oxide colloid, known by the commercial name of Ferumoxides and by the formulation name of Feridex, shows a shadow-generating effect in nuclear magnetic resonance computer section imaging or MRI. The tendency of this substance to accumulate in the liver is utilized in liver contrast medium used for the local diagnosis of liver cancers, and this agent has been approved by the decision of the First Survey Council for New Drugs and the Special Council for Drugs. Besides Feridex, other known fine magnetic particles include MnZn ferrite, Fe3O4 magnetite and the like; however, only Feridex has been tested with respect to side effects on the human body, and received approval.
Theoretically, it would appear to be possible to identify the positions of sentinel lymph nodes in three dimensions by injecting these existing magnetic fluids into areas proximal to malignant tumors, and then obtaining images by MRI after a fixed period of time has elapsed. In many cases, however, the chest must be opened in order to inject the magnetic fluid into the area proximal to a malignant tumor, and because of the flow velocity of the lymph, MRI imaging must be performed within a few minutes following injection. Since the MRI apparatus itself generates an intense magnetic field, this apparatus must be kept far away from equipment and instruments that possess magnetism, and therefore cannot be installed in the operating theater. Moreover, since the lymph nodes are scattered over a broad area, the imaging range of the sectional images must also be set over a broad range, so that the imaging time is increased. In addition, such imaging cannot be completed within a few minutes following injection. For these and other reasons, this method is not utilized to identify the positions of sentinel lymph nodes.
In order to popularize sentinel lymph node biopsies, it is necessary to make it possible to identify the positions of such lymph nodes in a short time by a non-invasive measurement method using a magnetic fluid as a marker, without using radioactive isotopes. However, in the case of methods that measure the residual magnetism of a magnetic fluid, there are many theoretical and practical restrictions. The reasons for these restrictions are as follows: as the particle size decreases, the residual magnetism characteristics are also diminished, so that the magnetic signal strength that is measured drops, and the problem of magnetic environmental noise is increased. In addition, there is some physical inconvenience involved in the method used to attach the excitation coil to the living-body tissue. Moreover, because the magnetic fluid is a liquid, the orientation of the magnetic moment quickly becomes disordered following magnetization as a result of the molecular motion of the fine magnetic particles, so that the magnetic field strength attenuates.